Oxo-s-hydroxydecanoic acid lactone

ABSTRACT

THE INTERMIDATES AND PROCESSES OF THIS DISCLOSURE PROVIDE A NEW STEREO-SPECIFIC TOTAL SYNTHESIS OF STEROIDAL MATERIALS HAVING KNOWN VALUABLE PHARMACOLOGICAL PROPERTIES. A FUNDAMENTAL FEAURE OF THIS DISCLOSURE IS THE UTILIZATION OF ARYL KETALS, PREFERABLY PHENYLENEDIOXY KETALS DERIVED FROM CATECHOL AS PROTECTIVE GROUPS FOR OXO MOIETIES IN THE POLYCYCLIC INTERMEDIATES USED IN THE AFORESAID TOTAL SYNTHESIS.

United States Patent Ofii ce Re. 28,099 Reissue-d Aug. 6, 1974 ABSTRACT OF THE DISCLOSURE The intermediates and processes of this disclosure provide a new stereo-specific total synthesis of steroidal materials having known valuable pharmacological properties. A fundamental feature of this disclosure is the utilization of aryl ketals, preferably phenylenedioxy ketals derived from c-atechol as protective groups for oxo moieties in the polycyclic intermediates used in the aforesaid total synthesis.

DETAILED [DESCRIPTION OF THE INVENTION This invention is concerned with certain polycyclic compounds and with processes for their synthesis. More particularly this invention relates to novel derivatives of cyclopent-a[f] [1]-benzopyrans and 7H-naphtho[2, 1-b] pyrans, and to methods for their production. These compounds are useful as intermediates in syntheses of steroids and D-homosteroids, respectively. in syntheses of steroidal materials steric considerations are of great significance. The most used steroidal compounds are those having a CID-trans ring junction with the substituent in the 13-position being in the fl-stereoconrfiguration. The present invention provides a facile total synthesis of 13,6-C/D-trans-steroidal materials. This desirable result is obtained via a unique asymmetric induction with optical specificity preserved in subsequent reaction steps. A particular aspect of this invention resides in the use of arylenedioxy ketals as protective groups for intermediate compounds in the synthesis of steroids. tArylenedioxy ketals exhibit unexpected advantages over other ketal protective groups, e.g., alkylenedioxy ketals in that the former groups are more stable to the reaction conditions employed in the synthesis thus providing substantially higher yields of desired end products. This is particularly true in the case of steps requiring oxidation in the presence of acid.

In a major aspect, this invention is concerned with novel derivatives of cyclopenta[f][1] benzopyrans having the tricyclic nucleus and novel derivatives of naphthoMJ-b] pyrans having 7 the tricyclic nucleus These novel compounds are generally defined by the formula:

wherein Y is B is the remaining residue of an aryl group which may be monocyclic or bicyclic and which may bear one or more additional substituents selected from the group consisting of lower alkyl and lower alkoxy; R, is a primary alkyl group of from 1 to 5 carbon atoms; R, is hydrogen, lower primary alkyl, or lower acyl; R R R R and R are each independently hydrogen or lower alkyl; Z is carbonyl or a group of the formula R is hydrogen or lower acyl; R is hydrogen or lower aliphatic hydrocarbyl; T represents either a single or a double bond; U represents a single or a double bond and is a single bond when T is a single bond; in is an integer having a value of l to 2; n is an integer having a value of from 0 to 11 and is 0 when T represents a double bond and is 1 when T represents a single bond; r is an integer having a value of from 0 to 1 and is 0 when T is a double bond and 1 when T is a single bond; and s is an integer having a value of from 0 to 1 and is 0 when U is a double bond and 1 when U is a single bond.

As used throughout the specification and appended claim, the term hydrocarbyl group denotes a monov-alent substituent consisting solely of carbon and hydrogen; the term hydrocarbylenc" denotes a divalent substituent consisting solely of carbon and hydrogen and having its valence bonds from diiferent carbons; the term aliphatic, with reference to hydrocarbyl or hydrocarbylene groups, denotes containing no aromatic unsaturation, but which can be otherwise saturated or unsaturated, i.e., an alkyl or alkylene, or an aliphatic group containing oleiinic or acetylenic unsaturation; the term alkyl group denotes a saturated hydrooarbyl group, whether straight or branched chain; the term primary alkyl group" denotes an alkyl group having its valence bond from a carbon bonded to at least two hydrogens; the term alkoxy denotes the group R'O, where R is alkyl; the term acyl group" denotes a group consisting of the residue of a hydrooarbyl monocarboxylic acid formed by removal of the hydroxyl portion of the carboxyl group; the term oxyhydrocarby denotes a monovalent saturated cyclic or acyclic group consisting of carbon, hydrogen, and oxygen containing only one oxygen in the form of an ether linkage; and the term lower as applied to any of the foregoing groups denotes a group having a carbon skeleton containing up to and including eight carbons, such as methyl, ethyl, butyl, tert.-butyl, hexyl, Z-ethylhexyl, vinyl butenyl, hexenyl, ethynyl, ethylene, methylene, formyl, acetyl, 2-phenylethyl, benzoyl, methoxymethyl, l-methoxyethyl, tetrahydropyran- 2-yl, methoxy, ethoxy, and the like.

In the formulas presented herein the various substituents on cyclic compounds are joined to the cyclic nucleus by one of three notations, a solid line indicating a substituent which is in the fi-orientation (i.e., above the plane of the paper), a dotted line indicating a substituent which is in the tit-orientation (below the plane of the paper) or a wavy line ---w) indicating a substituent which may be in either the aor B- orientation. The position of R, has been arbitrarily indicated as the fl-orientation, although the products obtained in the examples are all racemic compounds unless other wise specified.

Preferred compounds are those wherein Y is 3,3- (arylenedioxy)butyl wherein the arylenedioxy group, when taken with the 3-carbon of the butyl radical, forms a dioxolane ring system, especially 3,3-(phenylenedioxy)- butyl; R, is n-alkyl, especially methyl and ethyl; and when s has a value of 1, the 91:- (when m is l) or 10w (when m is 2) hydrogen is trans-oriented with respect to R1.

Subgeneric to the tricyclic compounds of Formula I are the 3 substituted fiafi-alkyl-1,2,3,5,6,6a,7,8-octahydro cyclopenta[f] [l]benzopyrans (by alternate nomenclature 3 substituted 6aB-alkyl-2,3,5,6a,8-hexahydro-1H-cyclopenta[f][l]-benzopyrans) and the 3-substituted-6aflalltyl 1,2,5,6,6a,7,8,9 octahydro 2H-naphtho-[2,l-b] pyrans (by alternate nomenclature 3substituted-6afl alkyl l,2,3,5,6,6a,8,9 octahydro 7H naphtho[2,l-b] pyrans), hereinafter referred to as dienes, having the formula:

tenant 0 YCHMMI En (la) wherein R R R Z, Y, and m are as defined above; the 3 substituted 621,8 alkyl-l,2,3,5,6,6a,7,9,9,9a-decahydrocyclopentalf][l]benzopyrans (by alternate nomenclature 3 substituted 6afl alkyl 1,2,3,5,6,6a,8,9,9aoctahydro 1H cyclopenta[f] [1]benzopyrans) and the 3-substituted 6a,8 alkyl-l,2,5,6,6a,7,8,9,10,10a decahydro 3H naphtho[2,l-b]pyrans (by alternate nomenclature 3 substituted 6a 3 alkyl-1,2,3,5,6,6a,8,9,10,10adecahydro 7H-naphtho[2,1-b]pyrans), hereinafter referred to as monoenes" represented by the formula:

YCHW Rn wherein R R R, Z, Y, and m are as defined above; and the 3 substituted 6a 8 alkyl-4a-hydroxyperhydrocyclopenta[f] [llbenzopyrans and the 3 substituted-6a alkyl 4a hydroxyperhydro 3H naphtho[2,1 b] pyrans and their lower alk l ethers and monoacyl esters,

Cit

' ;,4 a hereinafter referred to as perhydrducompounds, represented by the formula:

general reaction scheme:

R1 "|=1O l/(onum (III) 0 H YCIIp k/ R wherein Y, R R R R Z, and m are as defined above; and V is hydrogen, lower alkyl or lower acyl.

Thus, the process of this invention comprises the general steps of (1) condensation of a substituted 7-hydroxy- 1-alken-3-one or a variant thereof (II), as defined below, with a Z-aIkyl-cycloalkane-l,3-dione (III), as defined below, to produce diene (Ia); (2) saturation of the 9,9aor 10,10a-double bond of diene (Ia) to produce monoene, (Ib); and (3) introduction of a hydroxy, alkoxy, or acyloxy group at the 4a-position and a hydrogen atom at the 9bor IOb-position of monoene (Ib) to produce perhydro compound (Ic). It is to be understood that the foregoing reaction sequence is merely schematic in nature, and that each depicted step can represent only one or more than one reaction, as will be more fully described herein.

1-alken-3-one compounds of Formula II are employed as one of the starting materials for the foregoing reaction sequence. Illustrative examples of these l-alken-3-ones Yomdnhndnoniiicnflin,

include the 11,1l-arylenedioxy-7-hydroxy-l-alken-3-ones, preferably 11,11 phenylenedioxy-7-hydroxy-l-dodecen-Iione.

The 11,1l-arylenedixoy-7-hydroxy-l-dodecen-3-ones of Formula II above or cyclic variations thereof are readily synthesized from 4,4 ethylenedioxy-l-chloropentane as per the following reaction sequence:

CH0 CH0 8)! s):

HO OIRM I OH l vinyl 0 Grignard O OH C B (8) [[0] lMnOzRmH l 0m=oHM x -0 or variant l I CHg=CHMgX B O o :1 l on H 0 O B where B is as above, C is alkylenedioxy, preferably ethylenedioxy or arylenedioxy, preferably phenylenedioxy, X is a halide, preferably chloride, R is as hereinafter described and R is lower alkyl.

As indicated in the above sequence in one embodiment 4,4-alkyleneor phenylenedioxy-l-chloropentane (a) is converted to the Grignard by treatment with magnesium metal and the Grignard is then reacted with glutaraldehyde (b) to yield a hemiacetal (c). This reaction may be activated by the addition of a crystal of iodine to the reaction medium. Conversion of this hemiacetal to Formula 11 compounds may be accomplished by alternative routes. In a first route, where C is B, the hemiacetal (c) is reacted with vinyl Gringard in an ethereal solvent, e.g., tetrahydrofuran at -20 to 10 C. to yield the vinyl hydroxy compound (g). Treatment of (g) with manganese dioxide and R at room temperature in a hydrocarbon solvent yields compounds of Formula II.

The hemiacetal (c) may also be oxidized utilizing a chemical oxidizing agent, e.g., bromine or potassium dichromate to yield the lactone (d). It is preferable that when the ketal moiety C is arylenedioxy that the oxidizing agent used be other than bromine due to the possibility of bromination of the aromatic ring. When C is arylenedioxy in lactone (d), the lactone may be converted directly to compounds of Formula II by reaction with vinyl Grignard in ethereal solvent, e.g., tetrahydro- 6 furan at temperatures below 0, preferably --70 C. to 45 C.

Where C in lactone (d) is alkylenedioxy, the lactone is treated with aqueous acid to hydrolyze the ketal group to form the keto lactone (e). Treatment of the keto lactone with the desired dihydroxy aryl compound such as, for example, catechol or a 1,2- or 2,3-naphthdiolpreferably in an inert organic solvent, e.g., an aromatic hydrocarbon such as bezene, toluene or xylene, preferably benzene under conventional conditions, e.g., at reflux.

The aforesaid ketalization reaction may produce a ketal half-ester as an intermediate which is readily convertible into the desired arylenedioxy lactone upon distillation.

Compounds of Formula II are then obtained from said arylenedioxy lactones (f) by the selective addition of vinyl Grignard, e.g., vinyl magnesium chloride to the lactone at low temperatures, e.g., below 0 0., most preferably at about 45 C. in an inert organic solvent medium such as an etheric solvent, preferably diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or the like.

In an alternative procedure, ketal lactones of Formula d wherein C is B may be conveniently prepared from the arylenedioxyketal (h) by reaction with a S-oxo-pentanoic acid ester, e.g., the ethyl ester at a temperature of about 60 C. to 30 C., in tetrahydrofurau.

Because of the susceptibility of the vinyl group of the 7-hydroxy-l-alken-3-one to decomposition, it is desirable, although not essential, that this compound be converted to more stable variants, such as those of the formula:

0 O YCHK HCHCHCHlH CH Rm A n 11 (Ha) wherein R R Y and V are as defined above; and R is chloro, hydroxy, lower alkoxy, lower hydrocarbylamino or di(lower hydrocarbyl) amino.

As exemplary, these compounds of Formula IIa are readily produced from the vinyl ketones of Formula II by known techniques. For example, l-chloro-7-hydroxyalkan-3-ones are obtained by the anti-Markownikoff reaction of the vinyl compound with hydrogen chloride in known manner. l-hydroxy and l-alkoxy derivatives are obtained by the base-catalyzed reaction of water or a lower alkanol, for example, methanol, with the vinyl ketone. Additional derivatives are formed by the reaction of the vinyl ketone with a mono(lower hydrocarbyl)- or di(lower hydrocarbyl)-amine to form the Manuich base l-(lower hydrocarbyl)aminoor l-di(lower hydrocarbyl)amino-7-hydroxyalkan-3-one. A particularly advantageous procedure is to oxidize a hydroxyl vinyl compound e.g. Formula g with manganese dioxide in the presence of such an amine. In some instances, particularly in large scale commercial operation, it may be desirable to convert the Manuich base to its crystalline acid addition salts, particularly quaternary ammonium salts. All of the chloro, hydroxy alkoxy and aminoalkanones yield the alkenones of Formula II under the conditions of the condensation with the 2-alkylcycloalkane-1,3-dione.

The compounds of Formula H as is evident from the previously described reaction sequence can be used in the form of still another variant. This is the cyclized variant comprising a cyclic hemiltetal, i.e., Z-tetrahydropyranol of the formula:

YCH uwRu wherein Y is as defined above and R is lower hydrocarbylamino or di(lower hydrocarbyl)amino. The variants of Formula IIb can be prepared from compounds of Formula II by reaction with the same reactants as are used to produce those compounds of Formula Ila wherein R is lower hydrocarbylamino or di(lower hydrocarbyl)amino. As is apparent, those compounds of Formula Ila wherein R has the aforesaid meanings and the compounds of Formula IIb are isomers. These isomers exist in the form of a ketone of Formula Ila or in the form of the cyclic hemiketal of Formula IIb or as an equilibrium mixture of the two forms. Whether a particular Mannich base of Formula 1121 exists in that form or the hemiketal form or in an equilibrium mixture consisting primarily of one or the other will depend upon the environmental conditions in which it is placed, such as temperature, solvent, and pH of reaction medium, as well as the particular meaning of Y and R or R Either form is useful for the purposes of this invention since these isomers are used in a reaction with compounds of Formula III, infra, and either the acyclic form of Formula Ila or the cyclic hemiketal form of Formula 11b is useful for this purpose. A particular advantage of the cyclic form is its greater stability as compared with the acyclic form and also as compared with the vinyl ketones of Formula II. In order to obtain the cyclic form it is essential that in the compound of Formula IIa, V is hydrogen. Acidic conditions shift the equilibrium away from the cyclic form. Use of an optically active amine, e.g., aphenylethylamine, offers the advantage of resolving the compound, for example, via salt formation, to give an optically pure isomer of Formula 1121 or IIb which is then used in the remainder of the reaction sequence of this invention and when coupled with the unique asymmetric induction and preservation of optical specificity thereof offers a facile route to optically pure steroidal materials.

As is indicated above, the 7-hydroxy group of the 7- hydroxy-dodecanone of Formula II or Ila can be esterified or etherified for the condensation reaction with the cycloalkanedione. These reactions can be effected in known manner. For example, the 7-hydroxyalkan-3-one can be reacted with a carboxylic acid or an acid chloride to produce an ester, or can be converted to an ether by either (1) preferably, known acid catalyzed etherifications, e.g., with isobutylene or dihydropyran or (2) conversion of the 7-hydroxyalken-3-one to its sodium salt followed by reaction of the salt with an alkyl halide. In the event R is hydrogen, this hydroxyl group is also etherified or esterified.

The starting material of Formula II or variant thereof can either be used in racemic form or in optically active form. When used in optically active form, the 7S-antipode is preferred for reasons more fully explained below.

The second reactant employed in the condensation as generally mentioned above is a 2-(lower alkyl)cycloalkane-l,3-dione of the formula:

wherein R and m are as defined above.

These compounds are known compounds and description of their synthesis is accordingly unnecessary. Suitable compounds, include Z-methylcyclopentane-l,3-dione, 2-ethylcyclopentane-l,3-dione, 2 propylcyclopentane-1,3- dione, Z-butylcyclopentane-1,3-dione, Z-methylcyclohexane-1,3-dione, and the like.

The conditions for the condensation of ketone (II) or variant (Ila or IIb) with cyclic dione (III) are not narrowly critical, although it is preferred, particularly when the acyclic ketone is charged as the vinyl ketone, that a non-oxidizing atmosphere, e.g., nitrogen or argon, be employed. It is further preferred that an antioxidant, for example, phenolic compounds such as hydroquinone, be

(III) present. Furthermore, the. reaction can be conducted in the absence or presence of acid or base promoters. Suitable basic promoters include those heretofore known to promote the Michael condensation, including inorganic bases, for example, alkali metal hydroxides, such as so dium hydroxide or potassium hydroxide, and organic bases, including alkali metal alkoxides, for example, sodium or potassium methoxide or ethoxide, and ammonium hydroxides, particularly benzyltrialkylammonium hydroxide. A preferred class of base promoters are the amines, especially tertiary amines and most preferably pyridinetype compounds such as pyridine and the picolines. Acid promoters which can be employed include organic carboxylic acids such as acetic acid or benzoic acid; organic sulfonic acids such as p-toluenesulfonic acid; and mineral acids such as sulfuric acid, phosphoric acid, hydrochloric acid, and the like. The amount of promoter employed is not narrowly critical and can vary from catalytic amounts to molar amounts.

The ratio of ketone (II) or variant (Ila or Ilb) to cyclic dione (III) is not narrowly critical, although approximately equimolar amounts are preferred. Although there is no particular advantage to the use of excesses of either reactant, the cycloalkanedione can be more readily employed in excess because, due to its general low solubility in known organic solvents, unreacted cyclo alkanedione can be easily recovered from the reaction mixture.

The reaction temperature is not critical and can vary from room temperature or below to reflux temperature or higher. The condensation is preferably conducted in the presence of an inert solvent to insure a fluid reaction mixture and uniform reaction temperatures. Suitable solvents include tertiary alcohols such as tert.-butanol; aliphatic and aromatic hydrocarbons such as cyclohexane, hexane, octane, benzene, xylene, toluene, and the like; ethers such as diethyl ether, tetrahydrofuran, and the like; chlorinated hydrocarbons such as carbon tetrachloride, chloroform, and the like; as well as dipolar aprotic solvents such as dimethyl sulfoxide and the N,N-disubstituted amides such as dimethylformamide or dimethylacetamide.

The product of the condensation, depending upon the nature of vinyl ketone or variant (II, IIa or IIb) and/or the reaction promoter employed, can be one or more of the compounds having the formulae:

YCH I! (Ia-l) wherein R R R V, Y, and m are as defined above.

When vinyl ketone (II) is a 7-alkoxy or 7-acyloxy compound, the product will be a compound of Formula IV. However, when the vinyl ketone is a 7-hydroxy compound, or the reaction conditions are sufiicient to convert a 7-alkoxy or 7-acyloxy group, if present, the product will depend upon the promoter.

When the promoter is an acid or a relatively weak base, such as pyridine, or when no promoter is employed at all, the reaction product obtained from the 7-hydroxy vinyl ketone is the diene, i.e., tricyclie enol ether (Ia1). When a strong base, such as sodium or potassium hydroxide, is employed as a promoter, a crystalline product having the Formula VI is isolated, although compounds of Formulae IV and V are also present in the reaction mixture. However, the compounds of Formulae IV, V and VI, upon treatment with an acid, such as acetic acid, para-toluenesulfonic acid, or sulfuric acid, readily form the diene, i.e., tricyclic enol ether (Ia-1). It should also be noted that the conversion of the acyloxy or alkoxy groups of compound (IV) to a hydroxy group in an acidic medium is accompanied by cyclization to enol ether (Ia-1).

The condensation of a vinyl ketone of Formula II or a variant thereof of Formula IIa or III) with a cycloalkanedione of Formula III is one of the key features of this reaction. It is in this condensation that specific stereochemical induction at one member of the critical C/D- ring junction of the eventual steroidal product occurs. Thus, this invention is particularly advantageous in that it involves a unique asymmetric induction. Thus, the products of the condensation, i.e., the dienones of Formula Ia- 1, have at least two asymmetric centers at positions 3 and 6a permitting theoretically of two racemates or four optical antipodes. However, as a result of the condensation of this invention, when using a racemic starting material of Formulas II, Ila, or IIb wherein R and R are both hydrogen only a single racemate of Formula Ia-l results and when using an optically active starting material of Formulas II, Ila, or IR) wherein R and R are both hydrogen only a single optical antipode of Formula Ia-l results. It has further been found that when starting with a compound of Formula II or Ila with a 7S-stereoconfiguration or of Formula IIb with corresponding stereoconfiguration there is obtained the more desirable optical antipode of Formula Ia-l having a Gafl-stereoconfiguration. Thus, to prepare steroidal materials having the more desired l3fi-stereoconfiguration by the synthesis of this invention one can either start with the antipode of Formula II, IIa, or IIb, which can be prepared by resolving a racemic compound of Formula II, IIa, or IIb, or one can resolve at some intermediate stage subsequent to the condensation with a cycloalkanedione of Formula III or one can resolve the end-product steroidal material. In any event, the unique asymmetric induction concurrent to the condensation of this invention renders the obtention of a single optical antipode as an end-product more facile. The simultaneous formation of the dienol ether of Formula Ia-l with the unique asymmetric induction is a special advantage of this invention.

The dienes of Formula Ia in the presence of water and acid, e.g., sulfuric acid in acetone, aqueous acetic acid or aqueous hydrochloric acid in dioxane, undergo acid hydrolysis to form indenones of the formula wherein R R R Y and m have the same meaning as above. The indenones of Formula Ia are themselves convertible to compounds of Formula Ia via dehydration, for example, via acid catalyzed azeotropic distillation in benzene. Suitable acid catalysts are p-toluenesulfonic acid, potassium bisulfate, boron trifluoride etherate and the like. This reversible hydrolysis of compounds of Formula Ia is useful in their preparation and purification. Thus, in instances where the direct purification of compounds of Formula Ia is diflicult it is often more facile to hydrolyze the compound of Formula Ia to a compound of Formula Ia, which can then be purified, for example, by chromatography, and subsequently be reconvertcd to the desired compound of Formula Ia via dehydration.

The ketodienes of Formula Ia-l are readily converted to the corresponding hit-alcohols and their esters are represented by the formula:

0R1 RI YCHw k/ Rn E R1: (Ia-2) wherein Y, R R R R13 and m are as previously defined, by the sequence of reactions comprising reduction of the ketone to the alcohol and, if desired, subsequent esterification.

The reduction can be effected by any of the known methods for the chemical reduction of a ketone, e.g., by reaction of dienone (Ia-l) with an alkali metal or Group III-metal reducing agent. By the term alkali metal, as employed herein, is meant a Group I-rnetal having an atomic number of from 3 to 19, inclusive, i.e., lithium, sodium, and potassium. Group III-metals include those having atomic numbers of from 5 to 13, inclusive, i.e., boron and aluminum. Illustrative examples of these reducing agents include an alkali metal, preferably lithium or sodium, in liquid ammonia or a liquid aliphatic amine; tri(lower alkoxy)-aluminum compounds such as triisopropoxylaluminum; di(lower alkyl)-aluminum hydrides such as diethylaluminum hydride and diisobutyl-aluminum hydride; alkali metal-Group III-metal complex hydrides such as lithium aluminum hydride, sodium aluminum hydride, and sodium borohydride; tri(lower alkoxy)alkali metal-Group III-metal complex hydrides such as trimethoxy lithium aluminum hydride and tributoxy lithium aluminum hydride; diisobutyl aluminum hydride and the like. The alkali metal-Group III-metal complex hydrides are preferred as reducing agents, with the nonalkaline reagents, such as lithium aluminum hydride, being especially preferred.

This reaction is effected in any suitable inert reaction medium, such as hydrocarbons, e.g., cyclohexane, benzene, toluene, and xylene; ethers, e.g., diethyl ether, diisopropyl ether, and tetrahydrofuran. Protic solvents, such as Water or alcohols, should not be employed when lithium aluminum hydride is the reducing agent, but can be employed with sodium borohydride.

The remaining reaction conditions are not narrowly critical, although it is generally preferred to elfect the reduction at reduced temperatures, i.e., below about room temperature (about 2025 C.). Temperatures in the range of from about C. to about room temperature the normally employed.

The free alcohol is recovered from the reaction mixture after treatment of the mixture with acid. The alcohol can be esterified in known manner, for example, by base-catalyzed reaction with a carboxylic acid halide or carboxylic acid anhydride. Illustrative bases include inorganic bases such as sodium hydroxide and potassium hydroxide and organic bases such as a sodium alkoxide or an amine, especially a tertiary amine, and more particularly, pyridine and the picolines.

The ketodienes of Formula Ia1 can also be converted to their 7B-hydroxy-7[Jr-hydrocarbyl derivatives represented by the formula:

YCHg MAR."

Ru (Ia-3) wherein Y, R R R R and m are as previously defined and R is lower hydrocarbyl by reaction of the ketodiene with a Grignard reagent of the formula:

sMgX (VI wherein R is as previously defined and X is a halogen having an atomic number of from 17 to 35, inclusive (i.e., chlorine or bromine).

This Grignard reaction is conducted in known manner. For example, the Grignard reagent is prepared by react ing a hydrocarbyl halide with magnesium in an ether reaction medium, for example, ethyl ether or tetrahydrofuran, at elevated temperature, generally in the range of from about 40 C. to about 75 C. The ketodiene (Ia-l) is then added to the Grignard solution at about room temperature, although higher or lower temperatures can be employed. The resulting reaction product is hydrolyzed to produce the free alcohol, which can be esterified as discussed above.

Alternatively, the alcohols can be prepared by reaction of ketodiene (Ia-1) with a hydrocarbyl alkali metal compound such as methyl lithium, sodium acetylide, potassium acetylide, and the like.

The second step of the general synthesis of the tricyclic compounds of this invention comprises conversion of the dienes of Formula Ia to the monoenes of Formula lb by catalytic hydrogenation. Suitable catalysts include the noble metals, such as platinum, palladium, rhodium, and the like, as well as Raney nickel and other hydrogenation catalysts. These catalysts can be employed in the form of the metal alone, or can be deposited on suitable support materials, such as carbon, alumina, calcium carbonate, barium sulfate, and the like. Palladium and rhodium are preferred as catalysts. The hydrogenation is preferably conducted in the presence of inert solvents such as hydrocarbons, alcohols, ethers, and the like. The reaction conditions of pressure and temperature are not narrowly critical, and normally a hydrogen pressure of about one atmosphere and a temperature of about room temperature are employed. These ambient conditions are generally preferred to avoid significant hydrogenation of the 4a,9b(l0b)-double bond, although more severe con ditions, for example, up to about 100 C. and up to about 100 atmospheres, can be employed if desired. The hydrogenation medium can be acidic, neutral, or basic, as may be desired, although neutral media, such as hydrocarbons, e.g., toluene or hexane, or basic media, such as an alcohol-base, e.g., methanol-sodium hydroxide, mixture are preferred for best results. In general, hydrogenation of the diene of Formula Ia leads to the corresponding monoene of Formula Ib. However, in the event R is an unsaturated hydrocarbyl radical, the hydrogenates, in addition to hydrogenating the ring double bond, also hydrogenates the Win-hydrocarbyl substituent, converting it to an alkyl group.

Via the aforesaid catalytic hydrogenation C/D-trans compounds are formed in a major proportion when hydrogenating a diene of Formula Ia2. This method thus provides an advantageous synthesis of C/D-trans steroidal materials. When hydrogenating a diene of Formula Ia-l, C/D-cis compounds are formed in a major proportion. This method thus provides an advantageous synthesis of C/D-cis steroidal materials.

Compounds wherein Z is carbonyl, as represented by the formula:

R1: (1134) wherein Y, R R R and m are as previously defined, can be converted to the corresponding alcohols or esters of the formula:

OR: t

wherein Y, R R R R and m are as previously defined, or to the 7p-hydroxy-7tit-hydrocarbyl compounds of the formula:

Wherein Y, R R R R R and m are as previously defined, by the techniques discussed above regarding the dienes of Formula Ia.

When Z is carbonyl and the hydrogenation is effected under basic conditions, there is a tendency toward the production of predominantly the 6a/9a(10a)-cis-compound; that is, the hydrogen atom in the 9a(l0a)-position of Formula lbl is predominantly in the p-orientation. When these compounds are intended as intermediates for the synthesis of steroids having the C/D-trans-orientation, this technique is not particularly desirable. Although the ratio of fito a-orientation falls to about 1:1 at neutral conditions when hydrogenating a compound wherein Z is carbonyl, it is preferred to hydrogenate a 'ifl-alcohol or ester of Formula Ia-2 because the products of this hydrogenation are predominantly the 6a/9a(10a)-transcompounds. Compounds of Formula Ia-3 when subjected to the hydrogenation yield a ratio of to tit-orientation in between that of the compounds of Formula Ia-l and that of the compounds of Formula Ia-2. When monoenes of Formula Ib-l having C/D-trans-configuration are desired, it is preferable to first reduce the dienone of Formula Ia-l to a corresponding hydroxy compound of Formula Ia-2 prior to the catalytic hydrogenation. Following the catalytic hydrogenation the carbonyl moiety in Formula Ib-l can be regenerated by conventional means, such as oxidation with CrO The monoene compounds of Formula Ib prepared by the above-described hydrogenation contain at least three asymmetric centers, at positions 3, 6a and 9a when m is one and at positions 3, 6a and 10a when m is two. With respect to these three centers there are thus eight antipodal configurations possible. By virtue of the unique asymmetric induction of this invention, proceeding from a racemic starting material of Formula II, He or IIb only four of these antipodes of Formula Ib are prepared and proceeding from an optically active starting material of Formula II, Ila or IIb only two of these antipodes of Formula Ib are prepared. Moreover, by the above-described hydrogenation of this invention and by appropriate selection of the 7-substituent in the diene of Formula Ia subjected to the hydrogenation there can predominantly be prepared the desired 6a,9a(l0a)-transstereo-configuration. Thus, the eventual obtention of the more desired 1Sfi-C/D-trans-configuration in the ultimate steroidal products is rendered more facile by the stereoselective reactions provided by this invention.

The final reaction of applicants general process for the compounds of this invention is the conversion of the monoene of Formula Ib to the perhydro compound of Formula Ic by reaction of the monoene with a compound having the formula:

R OH

wherein R is as previously defined. That is, the monene of Formula lb is reacted with water, a primary alcohol, or a carboxylic acid. This reaction is catalyzed by mineral or organic acids, for example, hydrochloric acid, phosphoric acid, sulfuric acid, para-toluenesulfonic acid, and the like. Sulfuric acid is the preferred acid catalyst, and water the preferred reactant. Although not necessary, it is desirable to conduct this reaction in the presence of an added solvent, particularly in the event the compound of Formula VIII is water. In this case, it is desirable to employ a solvent which is both miscible with water and a solvent for the monene of Formula Ib. Solvents of this nature include, acetone, tert.-butanol, dioxane, and the like. The reaction temperature is not critical, and ambient temperature is normally employed, although higher and lower temperatures could be employed if desired.

As with the compounds of Formula Ia-l and Ib-l, the compounds of general Formula Ic wherein Z is carbonyl:

YCHINW wherein Y, R R R R and m are as previously defined, are readily converted to their corresponding alcohols:

wherein Y, R R R R R and m are as previously defined, by the previously described methods.

In a modification of the general technique outlined above, one can simultaneously effect the hydrogenation and hydration steps, for example, by hydrogenation of a diene of Formula la in aqueous sulfuric acid. When this simultaneous hydrogenation-hydroation reaction is effected, it is preferred to begin with a diene having a hydroxyl group in the 7,6-position.

As indicated above, the tricyclic compounds which form part of the present invention are useful as intermediates for the preparation of various steroid compounds, particularly 19-nor-steroids of the normal series, is illustrated by the following reaction scheme.

(XI) (XII) wherein R R R R R Y, Z and m are as above.

In the first step of this reaction scheme, the compound of Formula 10 is oxidized to form bicyclic compound of the Formula X by contact with such oxidizing agents as chromic acid, potassium dichromate, or potassium permanganate. Jones reagent (chromic acid, sulfuric acid and acetone), or a chromic acid-acetic acid mixture are preferred as oxidizing agents. The nature of Z is unchanged in this reaction, except when Z is hydroxymethylene [-CH(0H)]. In this instance, unless the hydroxyl group is protected, as by formation of a lower acyl ester, it is oxidized to form a carbonyl group. A hydroxylated product is readily obtained, however, by hydrolysis of a product ester. The reaction temperature is not narrowly critical, and temperatures in the range of from 0 C. to

15 about 75 C. are suitable, although ambient temperatures are preferred.

In the second step, bicycle compound (X) is treated with acid or base to effect cyclization to (XI). In this reaction, it is preferred that the water of reaction be removed, as by refluxing the reaction mixture with an azeotroping agent in the presence of a strong acid and separating the water from the condensate. Suitable strong acids are sulfuric acid, p-toluenesulfonic acid, potassium bisulfate and the like. Alternatively, base catalyzed dehydration can be utilized, for example, by refluxing compound (X) in the presence of methanolic sodium hydroxide.

The hydrogenation of cyclo-olefin XI is preferably effected with a noble metal catalyst, e.g. a palladium-charcoal catalyst or a rhodium catalyst. Mild conditions are generally employed, e.g., room temperature and atmospheric pressure are convenient conditions for this reac tion. The hydrogenated compound is converted to the desired l9-nor-steroid of Formula XII by heating it, preferably at reflux, with dilute aqueous acid, preferably a mineral acid such as hydrochloric acid in a lower alkanol solvent medium, preferably methanol.

Compounds of Formula XI wherein Z is carbonyl can be converted into corresponding pregnane compounds, i.e, compounds in which Z is of the formula CH i= by known procedures. Thus, for example, 19-nor-14fiandrost-4-ene-3,l7-dione can be converted into 19-nor- 14fi,l7a-progesterone. These procedures for converting androst-17-ones into pregnanes are best eflected if all carbonyl groups other than that in the 17-position are initially protected.

As has been pointed out above, the products of this invention are produced in the form of various optically active antipodes which can be carried through the entire reaction sequence, or which can be resolved at suitable places during the reaction sequence. For example, at any stage wherein a compound having a secondary hydroxyl group is present, such as hydroxytetrahydropyran (IV), or any of the hydroxy compounds of Formula I, one can react the secondary alcohol with a dicarboxylic acid to form a half-ester. Suitable dicarboxylic acids include lower alkyl dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, glutamic acid, adipic acid, or aromatic carboxylic acids such as phthalic acid. The resulting half-ester is then reacted with an optically active base, such as brucine, ephedrine, or quinine, to produce a diastereomeric salt. The salts, after separation, are then readily reconverted to optically active alcohols. As an alternative, the secondary alcohol can be reacted with an optically active acid, for example, camphorsulfonic acid. The resulting diastereomeric esters are then separated and reconverted to the alcohols.

It is preferred that the resolution be effected at some stage in the synthesis of alken-3-one, as by the abovementioned resolution of hydroxytetrahydropyran (IV). In a more preferred technique, optically active -alkyl-5- valerolactone is obtained from S-alkyl-S-oxopentanoic acid via known microbiological process. The S-form of this lactone is the preferred form for use in accordance with this invention. In a third method, the racemic lactone can be hydrolyzed to the corresponding hydroxy acid, which is then resolved by treatment with an optically active base in the manner described above. Still other methods will be apparent to those skilled in the art. Resolution at such early stages in the overall process described herein is highly preferred because of the improved efficiency in the production of steroids having a desired stereo-configuration. Because the stereoconfiguration is retained throughout the synthesis of alken-3-one (II), and

further, because the condensation of alken-S-one or variant (ll, Ila or IIb) with cycloalkanedione (III) is stereospecific, one, by proper selection of stereo-isomers at these early stages, can ensure that substantially all of the tricyclic compounds of this invention and the steroids derived therefrom have a selected stereo-configuration. Thus, by this technique, the production of compounds of the undesired configuration is minimized or prevented entirely, with an attendant increase in the efficiency of the production of compounds of the desired configuration.

In the claims, all compounds shall be construed to include, independently, the racemic form of the compound and independently, each enantiomeric form, i.e., the d and 1 configurations unless specifically indicated otherwise.

The following examples are illustrative. All temperatures are in degrees centrigrade and all products having centers of asymmetry are racemic unless specifically indicated otherwise.

EXAMPLE 1 (i)-9,9-ethylenedioxy-5-hydroxy-decanoic acid lactone 25 g. of the hemiacetal, (i)-6-[3-(2-methyl-l,3-dioxolan-2-yl)propyl] tetrahydropyran-Z-ol was dissolved in a mixture of dimethylformamide (DMF) acetic acidwatersodium acetate (anhydrous) (250 ml.; ml. H O/120 ml. DMF/4O ml. AcOH/24 g. NaOAc). Bromine (7 ml.) was then added to the cold (5-10) solution over 2-5 min. and the mixture was then stirred for a further 45 min. at room temperature. Aqueous sodium bisulphite solution and brine were then added and the organic products were isolated with benzene (5X ml.). The benzene extracts were washed with saturated brine solution (5X50 ml.) and then taken to dryness in vacuo. The crude lactone, (i)-9,9-ethylenedioxy-S-hydroxy-decanoic acid lactone yielded pure material on distillation B.P. 138-140/.42 mm.

In another experiment the hemiacetal, (:)-6-[3-(2- methyl-1,3-dioxolan 2 yl)propyl] tetrahydropyran-Z-ol gave the lactone, (i-)-9,9-ethylenedioxy-S-hydroxy-decanoic acid lactone, B.P. 141-145/.3 mm.

The starting material may be prepared as follows:

A solution of 2,Z-ethylenedioxy-S-chloropentane in tetrahydrofuran (THF) (50 ml.; 164 g. in 1600 ml. THF) was added to magnesium (38 g.) activated with a crystal of iodine. This mixture was stirred and heated at reflux until the reaction commenced. The rest of the chloroketal solution was then added over approximately 1 hr. to sustain gentle reflux. After complete addition, the mixture was stirred at room temperature for a further 2 hrs.

A solution of freshly distilled glutaraldehyde (110 g.) in THF (1000 ml.) cooled to 40 was treated with the above Grignard reagent (as rapidly as possible) and then stirred 30 min. at 30 and a further 1 hour at 0. Aqueous ammonia chloride solution (300 ml.; 25 percent) was then added and the products were isolated with ether. Removal of the solvents in vacuo gave the product as a mobile liquid (185 g.). This material was stirred at 50 with aqueous sodium sulfite solution (1500 mL; 20 percent) and the pH was adjusted first to pH 6.5 with acetic acid and then pH 7.5 sodium hydroxide solution (20 percent). The aqueous phase after stirring for 1 hr. at 50 was extracted with ether and then treated with caustic soda solution (20 percent) to pH 12. Extraction with benzene then furnished the hemiacetal (i )-6-[3-(2-methyl-1,3-dioxolan 2 yl)propyl]tetrahydropyran-Z-ol (118 g.) as a mobile, pale yellow liquid. A sample was distilled (molecular still) to give a colorless product, B.P. 132/.1 mm.

EXAMPLE 2 (il-9-oxo-5-hydroxydecanoic acid lactone 52.4 g. of the ketal lactone, (i)-9,9-ethylenedioxy-5- hydroxy-decanoie acid lactone dissolved in acetone ml.) was treated with water (75 mL), dilute aqueous sulphuric acid (2 N; 45 ml.) and left to stand at room tem- 1 7 perature for 16 hr. Addition of brine and extraction with benzene gave the crude lactone, (i)-9-oxo-5-hydroxydecanoic acid lactone which on distillation yielded pure material 98 percent pure by VPC B.P. 134/ .05 mm.

EXAMPLE 3 -9,9-phenylenedioxy-S-hydroxydecanoic acid lactone 15 g. of a solution of the ketolactone (:l-9-oxo-5-hydroxydecanoic acid lactone in benzene (300 ml.) was treated with 20 g. catechol and 0.6 g. p-toluenesulphonic acid (PTS). The mixture was heated at reflux under nitrogen in conjunction with a Soxhlet extraction apparatus equipped with a thimble filled with calcium hydride. After 18 hr. at reflux the mixture was cooled and chromatographed directly on silica gel (.2.5 mm. mesh; 650 g.). Elution with and ethyl acetate-benzene mixtures yielded the ketal ester.

Distillation of the above material gave catechol and the desired lactone, (i)-9,9-phenylenedioxy-5-hydroxydecanoic acid lactone, B.P. 152170/.2 mm. (This was a short path distillation and the majority of the material had B.P. l57162.) A sample of this material was redistilled (Kugel Rhor) and gave material, B.P. 14054/ .02 mm.

EXAMPLE 4 (t )-6-(4,4-phenylenedioxypentyl )-2- 2-diethylaminoethyl -tetrahydropyran-2-ol 1.6 g. of the ketal lactone, (i)-9,9-phenylenedioxy-5- hydroxy-decanoic acid lactone in tetrahydrofuran (THF; 15 ml.) was cooled to 45 and treated over 5 min. with a solution of vinyl magnesium chloride in THF (4.6 ml.; 2 moi/liter). After stirring a further min. at -45, methanol (5 ml.) was added followed by an aqueous ammonium chloride solution (15 percent; 20 ml.). The products were extracted into ether and the ether extracts then treated with diethylamine (5 ml.) and dried over magnesium sulphate. Removal of the solvents in vacuo gave the crude Mannich base which was separated from neutral material with dilute aqueous acid (1 N H 80 4x 15 ml.). The aqueous extracts were made basic with caustic potash solution and the products isolated with ether. Removal of the solvents in vacuo gave the Mannich base, (i)-6-(4,4-phenylenedioxypentyl) 2 (Z-diethylaminoethyl)-tetrahydropyran-2ol as a mobile liquid.

This material showed one spot on TLC analysis on development with a benzene/triethylamine (9:1) system.

EXAMPLE 5 (i) 3 (4,4-phenylenedioxypentyl)-6a,p-methyl-1,2,3,5,

6,6a hexahydrocyclopenta[f] [11benzopyran 7(8H)- one 10.6 g. of the Mannich base, (:)-6-(4,4-phenylenedioxypentyl) 2 (Z-diethylaminoethyl)-tetrahydropyran- 2-01 in toluene (80 ml.) was added rapidly to a refluxing solution of Z-methylcyclopentan-l,3-dione (4.7 g.) in toluene (50 ml.), acetic acid (23.2 ml.) and pyridine (7.2 ml.) under nitrogen. After heating at reflux for a total of 4 hr. (reaction followed by TLC) the mixture was cooled, diluted with toluene (100 ml.) and extracted with water (4x 50 ml.), saturated aqueous sodium bicarbonate solution (1X 50 ml.), brine (1 X 50 ml.) and dried over MgSO Removal of the solvents in vacuo yielded the crude crystalline dienolether, (:)-3-(4,4-phenylenedioxypentyl) 6a,}? methyl-1,2,3,5,6,6a-hexahydrocyclopenta[f][l])benzopyran-7(8H)-one, M.P. 115-120. A sample of this material was recrystallized from benzenehexane mixture to give pure material M.P. 126129.

EXAMPLE 6 (i)-3-(4,4-phenylenedioxypentyl)-6a,;8-methyl-1,2,3,5, 6,621,7,8-octahydrocyclopenta[f] [1]benzopyran'7,8-ol

10.7 g. of the crude dienolether, (:)-3-(4,4-phenylenedioxypentyl)ba e-methyl 1,2,3,5,6,6a hexahydrocyclopentafi][l]benzopyran-7(8H)-one dissolved in TI-IF/ ether ml; 1:1) was added to a slurry of lithium aluminum hydride (4 g.) in a THF/ether mixture (400 ml.; 1:1) cooled in an ice-salt bath (temp. held at -3). After complete addition the mixture was stirred for a further 10 min. at -5 and 1% hr. at room temperature (followed by TLC). Wet ether (100 ml.) was then added followed by a saturated aqueous solution of sodium sulphase (25 ml.). The coagulated salts were then filtered off, washed with THF and the filtrate was dried over MgSO. Removal of the solvents in vacuo gave the crude alcohol, (i )-3-(4,4-phenylenedioxypentyl )-6u,;3methyl- 1,2,3,5,6,6a,7,8 octahydrocyclopenta[f][l]benzopyran- 7,8-01.

EXAMPLE 7 (i) 3 (4,4 phenylenedioxypentyl)-6a,fl-methyl-l,2,3, 5,6,6a,7,8,9,9a decahydrocyclopenta[fj [l]benzopyran- 73-01 11.2 g. of the crude dienolether alcohol, -)-3-(4,4- phenylenedioxypentyl-6a,fimethyl 1,2,3,5,6,6a,7,8-octahydrocyclopenta[f][l]benzopyran-7;8-ol (this still contains some solvent) was dissolved in toluene (100 ml.) treated with 2 g. of a 5% Pd/C catalyst and hydrogenated at room temperature and pressure. After 5% hr. the uptake of hydrogen stopped (635 ml.; theory 700 ml. at room temperature and pressure for 10.7 g.) and the solids were filtered oh and washed with toluene. Removal of the solvents in vacuo gave the enol ether, (i)-3-(4,4-phenylenedioxypentyl) 6a, B-methyl 1,2,3,5,6,6a,7,8,9,9a-dec ahydrocyclopenta[fl[l]benzopyran-7p-ol, as an oil.

EXAMPLE 8 )-4-(3-oxo-7,7-phenylenedioxyoctyl )-1a,l3-methylperhydroindan-1,5-dione 10.76 g. of the crude enol ether, (i)-3-(4,4-phenylenedioxypentyl) 6a,;i-methyl 1,2,3,5,6,6a,7,8,9,9a-decahydrocylopenta [f][1]benzopyran-7 S-ol dissolved in acetone (210 ml.) was treated with aqueous sulphuric acid solution (50 ml.; .5 N) and left at room temperature for 2 hr. (followed by TLC). Dilution with ether (500 ml.) and washing with brine (5X 100 ml.) and saturated aqueous sodium bicarbonate solution (1X 50 ml.) [all aqueous extracts were backwashed with ether (1x 100 1.)] gave the hemiketal, (i) 3 (4,4 phenylenedioxypentyl) 6a5 methyl 4 hydroxyperhydrocyclopenta [f][1]benzopyran-7B-ol as a glass.

This material was virtually pure by TLC and showed no enol ether band in the IR. The strong hydroxyl bands at 3450 and 3757 cm. and the characteristic catecholketal bands were most pronounced. 10.37 g. of this crude hydration product, was dissolved in acetone (200 ml.) cooled in an ice bath and treated at 05 with fresh Jones (5) chromic acid mixture (20 ml.) over 10 min. After stirring a further 1% hr. at room temperature, aqueous sodium bisulphite solution (100 ml.; 10%) and brine (100 ml.) were added and the organic materials were isolated with benzene (4x 200 ml.). The benzene extract was washed with brine and aqueous sodium carbonate solution (10%) to give the neutral triketone, (i 4 (3 oxo 7,7 phenylenedioxyoctyl) 1a,;3 methylperhydroindan 1,5 dione as a pale yellow liquid. This material showed one major spot on TLC and had bands in the IR spectrum (film) at 1730 cm. (cyclopentanone, 1705 CIIL'I (saturated carbonyl) and 1480, 1240 and 730 cm.- (catechol ketal).

oxo 7,7 phenylenedioxyoctyl) 1a,fl methyl perhydroindan 1,5 dione in methanol (250 ml.) containing 1 g. of potassium hydroxide was heated at reflux, under nitrogen, for 1 hr. (followed by IR). Benzene (500 ml.) was added and the mixture was extracted with dilute aqueous sulphuric acid (3X 50 ml. .5 N), saturated sodium bicarbonate solution of (1 X 100 ml.), brine and then dried over MgSO (note: all aqueous extracts were back washed with benzene). Removal of the solvents in vacuo furnished the crude tricyclic material, (i) 6 (3,3- phenylenedioxybutyl) 3a, 6 methyl 4.5,8,9,9a,9b-hexahydro ll-l benz[e]indene 3,7(2H.8H) dione as a semi-solid. This material was digested with ethanol (50 ml.) to give the crystalline material, M.P. 166-170".

A sample of this material was recrystallized from ethanol to yield pure colorless crystals, M.P. 173-175.

EXAMPLE 10 (i )-19-nor-androst-4-ene-3, l7-dione 4.01 g. of crude (i) 6 (3,3 phenylenedioxybutyl)- 3a, methyl 4,5,8,9,9a,9b hexahydro 1H benzlel indene 3,7(2H,8H) dione was dissolved in THF (45 ml.) containing triethylamine (.8 ml.) and 400 mg. of a percent Pd/C catalyst and hydrogenated at room temperature and pressure. After 6 hr., the uptake of hydrogen ceased (280 ml. consumed; theory 285 ml./RTP). The solids were filtered off, washed with THE and the filtrate was taken to dryness in vacuo. The crude hydrogenation product (some solvent residue) showed bands in the IR spectrum (film) at 1705 cm.- (cyclohexanone), 1735 cm. (cyclopentanone) and i480, 1240 and 740 cm. (catechol ketal) and was virtually one spot material on TLC. 4.3 g. of this crude hydrogenation material was dissolved in methanol (70 ml.) and 35 ml. of 4 N HCl and the solution was heated at reflux for 6 hr. (followed by TLC and ]R). The mixture was cooled, treated with benzene (200 ml.) and extracted with aqueous caus tic soda solution (1 N; 3 100 ml.) and brine (2X 50 ml.). (All aqueous extracts were backwashed with benzene.) Removal of the solvents in vacuo gave crude l9- nor-androst-4-en-3,17-dione which on crystallization from dichloromethane/isopropyl ether mixture yielded pure (i) l9 nor androst 4 -ene 3,17 dione, M.P. 155l57, identical in all respects with authenic (i)- l9-nor-androst-4-ene-3,7-dione, MP, MX MP, TLC, IR, and UV.

EXAMPLE 11 (i) 3-(4,4-phenylenedioxypentyl )-6a.fl-ethyll ,2,3,5.6, 6a-hexahydrocyclopenta[E] 1 }benzopyran-7(8H)-one (i) Z-(Z-diethylaminoethyl)-6(4,4 phenylenedioxypentyl)-tetrahydropyran-2-ol (3.8 g.) in toluene (20 ml.) was added to a refluxing solution of Z-ethylcyclopentan- 1,3-dione (2 g.) in toluene (40 ml.) and acetic acid (20 ml.) and heated at reflux for 1 hour.

Isolation of the organic materials with toluene gave pure (i) 3-(4,4-phenylenedioxypentyl)-6a,fi-ethyl-l,2,3, 5,6,6a hexahydrocyclopentafi][1lbenzopyran 7(8H)- one (2.95 g.) after chromatography on alumina.

EXAMPLE 12 )6-(3,3-phenylenedioxybutyl)-3a.B-ethyl-4.5,8,9,9a, 9b-hexahydro-l H-ben[e] inden-3,7-(2H,3aH)-dione Crude (i) 3-(4,4-phenylenedioxypentyl)-6a,;3-ethyl-1, 2,3,5,6,6a-hexahydrocyclopenta [f] 1]benzopyran-7(8H)- one (47 g.) dissolved in tetrahydrofuran (200 ml.) was added to a cold slurry of lithium aluminum hydride (6 g.) in tetrahydrofuran (200 ml.).

After stirring for 2 hours at room temperature, saturated aqueous sodium sulfate solution was added (40 m1.) and the solids were filtered ofl.

Removal of the solvents in vacuo gave racemic 3-(4,4- phenylenedioxypentyl)-6a, ethyl 1,2,3,5,6,6a hexahydrocyclopentafl][1]benzopyran-7;3-ol as an oil (51 g.).

The above crude material was dissolved in toluene, treated with Pd/C (5%; 5 g.) and hydrogenated at room temperature and pressure until the hydrogen uptake stopped (approximately 30 hours).

The solids were filtered off and the solvents removed in vacuo to yield crude (i) trans-3-(4,4-phenylenedioxypentyl)-6a,l9-ethyl-l,2,3,5,6,6a,7,8.9,9a decahydrocyclopenta[fl[llbenzopyran-7;3-ol as an oil (48 g.).

The above material was dissolved in acetone (500 ml.) treated with dilute aqueous sulfuric acid (0.5 N; 50 ml.) and left to stand at room temperature for 2 hours. The solution was then cooled to 5 and treated over 30 minutes with fresh Jones chromic acid reagent (125 ml.). The mixture was then stirred for a further 2 hours at room temperature and then quenched with aqueous sodium bisulfite solution (20%; 50 ml.).

Isolation of the organic materials with benzene and extraction with aqueous sodium carbonate solution gave racemic trans-4-(3-oxo-7,7 phenylenedioxyoctyl) la,B- ethyl-perhydroindane-1,5dione (34.4 g.) after removal of the organic solvents in vacuo.

The crude bicyclic material (34.4 g.) was dissolved in methanol (110 ml.) and added to a refluxing solution of potassium hydroxide (3.5 g.) in methanol (200 ml.).

After 1 hour at reflux the organic materials were isolated with benzene and chromatography on silica gel (800 g.) gave racemic 6-(3,3-phenylenedioxybutyl)-3a,fiethyl-4,5,8,9,9a,9b-hexahydro 1H benz[e]inden 3,7- (2H,3aH)-dione (20 g.) as an oil.

EXAMPLE 13 (i) 13p-ethylgon-4-en-3,17-dione Racemic 6-(3,3-phenylenedioxybutyl)-3a-fi-ethyl-4,5,8, 9,9a,9b-hexahydro 1H benz[e]inden 3,7 (2H,3aH)- dione (20 g.) was dissolved in ethanol (250 ml.) containing triethylamine (2 ml.) and Pd/C (5%; 4 g.) and hydrogenated at room temperature and pressure until the uptake of hydrogen stopped.

The solids were filtered off and dilute aqueous hydrochloric acid (4 N; 200 ml.) was added and the mixture was heated at reflux for 5 hours.

The organic materials were isolated with benzene and the benzene extract was then washed free of catechol with dilute aqueous caustic soda solution.

Removal of the solvents in vacuo yielded a semisolid which on crystallization from dichloromethane-isopropyl ether mixture yielded pure racemic l3fl-ethylgon-4-en-3,

17-dione (6.3 g.) M.P. 159-161.

EXAMPLE 14 2R,6S-2[Z-(R-a-phenethylamino)ethyl] 6 (4,4-phenylenedioxypentyl) tetradropyran-Z-ol and 2S,6R-2[2 (R-tx-phenethylamino)-ethyl 6 (4,4 phenylenedioxypentyl) tetrahydropyran-Z-ol (i) 9,9-phenylenedioxy-S-hydroxy decanoic acid lactone 11.1 g.) dissolved in tetrahydrofuran ml.) at 50 was treated with vinylmagnesium chloride solution (39 ml.; 2 molar in THF) over 3 minutes. The mixture was then stirred at 45 for 25 minutes, quenched with methanol (10 ml.) and ammonium chloride solution (15%; 100 ml.) and extracted with ether.

Removal of the solvents in vacuo gave the crude vinyl ketone as an oil. This material was dissolved in benzene 20 ml.) and treated with a solution of a-phenethylamine (3.9 g.) in benzene (20 ml.) and left at room temperature for 3 hours.

The solvents were removed in vacuo and the residue extracted with hexane. This hexane extract was filtered through alumina (50 g.) to give the mixture of diastereomeric bases (11 g.) as a liquid.

This material was dissolved in hexane and left to crystallize. Recrystallization yielded the pure 2S,6R,2-[2-(R- u-phenethylamino)ethyl]6-(4,4 phenylenedioxypentyl)- tetrahydropyran-Z-ol, M.P. 72-76"; [m ]=+37 (c.=5, benzene).

The mother liquors from the first crystallization were taken to dryness and dissolved in acetone ml.). This solution was added to oxalic acid (2 g.) in acetone ml.) and left to crystallize.

Recrystallization of the solids from acetone yielded pure 2R,6S,2 [2 (R-a-phenethylamino)ethyl]-6-(4,4- phenylenedioxypentyl) tetrahydropyran 2 ol oxalate, M.P. [a ]==+21 (c.=1.248, methanol).

EXAMPLE l5 3S,6aS,3 (4,4 phenylenedioxypentyl) 6a,fl methyl-1, 2,3,5,6,6a hexahydrocyclopenta[f][1]benzopyran 7 (8H)-one 2S,6R 2[2 (R a phenethylamino)ethyl]-6-(4,4- phenylenedioxypentyl) tetrahydropyran-2-ol (1.25 g.) in toluene (45 m1.) and aqueous acetic acid (18 ml.; was treated with pyridine (9 ml.) and 2-methylcyclopenta-1,3-dione (0.5 g.) and heated at for 7 hours. After this time the water was taken off with a Dean- Stark separator (-45 minutes) and the mixture cooled.

Isolation of the materials with benzene and chromatography on alumina yielded the dienol ether.

Crystallization from hexane gave optically pure 3R,6aS, 3 (4,4 phenylenedioxypentyl)6a,fi methyl 1,2,3,5,6-

6a hexahydroeyclopentafi] [l]benzopyran 7(8H) one, M.P. 109-112, [a ]=--121 (c.=1.0, CHCI EXAMPLE 16 )-19-norandrost-4-en-3 ,17-dione References Cited The following references, cited by the Examiner, are of record in the patented file of this patent or the original patent.

UNITED STATES PATENTS 3,048,599 8/1962 Rosenmund et al. 260-343.S

DONALD G. DAUS, Primary Examiner A. M. T. TIGHE, Assistant Examiner 

